Clinical Trials /

YIV-906 (Formerly PHY906/KD018) With Sorafenib in HBV(+) Hepatocellular Carcinoma (HCC)

NCT04000737

Description:

YIV-906 (PHY906, KD018) is an oral form of a spray-dried aqueous extract of four herbs, which have been used in the Orient for more than 1800 years for a variety of gastrointestinal symptoms including diarrhea, nausea, and vomiting. Extensive clinical and pre-clinical research has been done indicated that YIV-906 may have synergistic anticancer activities as well as GI toxicity reduction to cancer treatments, including sorafenib. The proposed plan will investigate the efficacy and mechanisms of YIV-906 as an adjuvant to sorafenib in the treatment of patients with Hepatitis B(+)-associated advanced hepatocellular carcinoma.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: YIV-906 (Formerly PHY906/KD018) With Sorafenib in HBV(+) Hepatocellular Carcinoma (HCC)
  • Official Title: A Phase II Randomized Placebo-Controlled Study Investigating The Combination Of YIV-906 And Sorafenib (Nexavar®) In HBV (+) Patients With Advanced Hepatocellular Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: YIV-906-2018L1
  • NCT ID: NCT04000737

Conditions

  • Advanced Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
YIV-906+SorafenibSorafenib + YIV-906
Placebo+SorafenibSorafenib + Placebo

Purpose

YIV-960 (PHY906, KD018) is an oral form of a spray dried aqueous extract of four herbs, which have been used in the Orient for more than 1800 years for a variety of gastrointestinal symptoms including diarrhea, nausea, and vomiting. Extensive clinical and pre-clinical research has been done indicated that YIV-906 may have synergistic anticancer activities as well as GI toxicity reduction to cancer treatments, including sorafenib. The proposed plan will investigate the efficacy and mechanisms of YIV-906 as an adjuvant to sorafenib in the treatment of patients with Hepatitis B(+)-associated advanced hepatocellular carcinoma.

Detailed Description

      HCC patients with chronic HBV (+) (HBsAg(+) and IgM anti-HBc (-)), and Child-Pugh A status
      will be randomized to either the study arm (YIV-906 plus sorafenib) or control arm (placebo
      plus sorafenib). Patients will be stratified according to metastatic status
      (extrahepatic/vascular invasion vs. none), and their ECOG performance status (0 vs. 1) at
      randomization.

        -  ARM I: Patients receive Placebo + Sorafenib

        -  ARM II: Patients receive YIV-906+ Sorafenib

      Patients in the study arm will be treated orally each 28-day course with YIV-906 (600 mg (3
      capsules) BID) + sorafenib (400 mg BID) according to the following schedule: sorafenib BID
      daily treatment for 28 days, and YIV-906 BID 4 days on and 3 days off weekly in each course.

      All patients will be evaluated and graded for adverse events according to the NCI Common
      Terminology for Adverse Events, version 4.0 (CTCAE). The modified Response Evaluation
      Criteria in Solid Tumors (mRECIST) will be used to establish disease response or progression.

      Patients will be evaluated for PFS, TTP, OS, antitumor response, QoL and safety every two
      courses. Biomarkers are mandatory and will be studied prior to drug administration and day 1
      of every other cycle. Gut and oral microbiota studies as well as TCM Syndrome Research are
      optional.

      PK is only optional in China study sites, and limited to the first 15 male and 15 female
      patients. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio). PK
      studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12
      hours post-dose administration on Day 1 of Cycles 1.
    

Trial Arms

NameTypeDescriptionInterventions
Sorafenib + YIV-906ExperimentalPatients in the study arm will be treated orally for two 28-day courses with YIV-906 + sorafenib
  • YIV-906+Sorafenib
Sorafenib + PlaceboActive ComparatorPatients in the placebo arm will be given sorafenib with placebo
  • Placebo+Sorafenib

Eligibility Criteria

        Inclusion Criteria:

          -  Male or females ≥ 18 years old with the ability to take oral drugs

          -  Diagnosis of advanced HCC according to the American Association for the Study of Liver
             Diseases (AASLD) Guidelines (Heimbach et al. 2016) or diagnosis by tissue pathology

          -  Life expectancy of at least 3 months

          -  Presence of chronic hepatitis B (HBsAg (+), anti-HBc (+), IgM anti-HBc (-) and
             anti-HBs(-))

          -  Never received systemic antitumor therapy

          -  Patients must have at least one tumor lesion that meets both of the following
             criteria:

               -  "Measurable disease" according to mRECIST, i.e. at least one measurable lesion.

               -  The lesion has not been previously treated with local therapy

          -  Patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤1

          -  Cirrhotic status of current Child-Pugh class A. Child-Pugh status should be calculated
             based on clinical findings and laboratory results during the screening period

          -  For patients with positive HBV-DNA and/or positive HBsAg results, they must be treated
             with antivirals, as prophylaxis starting at least 1-2 weeks prior to receiving study
             drug

          -  Patients with adequate organ reserve, such as laboratory parameters:

               -  Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L

               -  Platelets ≥ 60000 x 10^6/L

               -  Hemoglobin (Hgb) ≥ 9 g/dL

               -  Serum alanine amino-transferase (ALT) ≤ 5 x ULN

          -  Adequate renal function, based upon meeting the following laboratory criteria within 7
             days before randomization:

               -  Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40mL/min (using
                  the Cockroft-Gault equation: (140-age) x weight (kg)/(serum creatinine x 72
                  [mg/dL] for males. (For females multiply by 0.85)

               -  AND

               -  Urine protein/creatine ratio (UPCR) ≤ 1 mg/mg (≤113.1 mg/mmol) or 24-hour urine
                  protein <1 g

          -  Ability to understand and willingness to sign a written informed consent and to be
             able to follow the visit schedule

        Exclusion Criteria:

          -  Patients who have received systemic chemo-therapies or immunotherapy or molecular
             target therapies

          -  Patients who have received any local anti-cancer therapy within 4 weeks

          -  Active bleeding (including gastrointestinal bleeding, encephalopathy, and ascites)
             during the last 4 weeks prior to Cycle 1

          -  Patients with a history of allergy to the known components of YIV-906

          -  Known history of human immunodeficiency virus (HIV) seropositivity

          -  Known central nervous system metastasis including brain metastasis and meningeal
             carcinomatosis

          -  Hepatocholangial carcinoma, fibrolamellar cell carcinoma and mixed hepatocellular
             carcinoma

          -  Active malignancy (except for definitively treated melanoma in-situ, basal or squamous
             cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 5
             years

          -  Any severe and/or uncontrolled medical conditions including:

               -  Unstable angina pectoris, symptomatic congestive heart failure, myocardial
                  infarction ≤ 6 months prior to Cycle 1 treatment, serious uncontrolled cardiac
                  arrhythmia, uncontrolled hypertension

               -  Previous transient ischemic attack (TIA), cerebral vascular accident (CVA),
                  symptomatic peripheral vascular disease (PVD) within last 6 months of Cycle 1
                  treatment

               -  Congenital long QT syndrome

               -  Patients with active alcohol intake

               -  Acute and chronic, active infectious disorders and nonmalignant medical illnesses
                  that are uncontrolled or whose control may be jeopardized by the complications of
                  this study therapy, in the opinion of the investigator, except chronic HBV or HCV

               -  Impairment of gastrointestinal function or who have a gastrointestinal disease
                  that may significantly alter the absorption of study drugs (e.g., ulcerative
                  disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)

               -  Patients who have had organ transplantation

          -  Patients receiving chronic treatment with corticosteroids (except for intermittent
             topical or local injection or aldosterone) or other immunosuppressive agent

          -  Patients treated with drugs known to be strong inhibitors or inducers of isoenzyme
             CYP3A

          -  Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or
             who have not recovered from surgery

          -  Patients who have received an investigational drug or therapy within the last 4 weeks
             prior to Cycle 1 treatment.

          -  Pregnant and/or breastfeeding women

          -  Men and women of childbearing age and potential, who are not willing to use effective
             contraception

          -  Unwilling or unable to follow protocol requirements or to give informed consent

          -  An ongoing or recent history of autoimmune, psychiatric disorders and drug abuse

          -  Uncontrolled hereditary or acquired thrombotic or bleeding disorder

          -  Bowel obstruction, history or presence of inflammatory enteropathy or extensive
             intestinal resection

          -  Therapeutic dose anticoagulation with warfarin, low molecular-weight heparin, or
             similar agents

          -  Chronic therapy with nonsteroidal anti-inflammatory agents or other antiplatelet
             agents. Aspirin at doses up to 100 milligrams/day is permitted

          -  Patients with an estimated or calculated baseline creatinine clearance of less than 30
             mL/min should not be enrolled in this trial

          -  No patient, however, may enroll in this trial if they are taking phenytoin (Dilantin)

          -  Patients taking traditional Chinese medicines within 14 days prior to enrollment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months.
Safety Issue:
Description:PFS is defined as the period elapsing between the date of date of randomization and the date of either disease progression or date of death, whichever is earlier.

Secondary Outcome Measures

Measure:Time to progression (TTP)
Time Frame:At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months.
Safety Issue:
Description:TTP is defined as the period elapsing between the date of randomization and the date of disease progression.
Measure:Overall survival (OS)
Time Frame:At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months.
Safety Issue:
Description:OS is defined as the interval between time of randomization and the date of death from any cause.
Measure:Objective response rate (ORR) in each arm
Time Frame:At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months.
Safety Issue:
Description:The modified Response Evaluation Criteria in Solid Tumors (mRECIST) will be used to establish disease response or progression
Measure:Disease control rate (DCR) in each arm
Time Frame:At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months.
Safety Issue:
Description:DCR will be defined as the proportion of patients achieving either partial response (PR) or complete response (CR) or stable disease (SD).
Measure:The safety and tolerability of the combination of YIV-906 plus sorafenib as measured by the rate and severity of AEs
Time Frame:Continuously throughout the study until 28 days after treatment discontinuation
Safety Issue:
Description:All patients will be evaluated and graded for adverse events according to the NCI Common Terminology for Adverse Events, version 4.0 (CTCAE).
Measure:Change of quality of life (QoL) in each arm with HCC18
Time Frame:At baseline and then at end of every course (4 weeks) until the end of study. Assessed up to 24 months.
Safety Issue:
Description:Each of the domains in the HCC18 will be scored per the assessment's scoring algorithm and summarized using descriptive statistics at baseline
Measure:Change of quality of life (QoL) in each arm with EORTC-C30
Time Frame:At baseline, and then at the end of every course (4 weeks) until the end of study. Assessed up to 24 months.
Safety Issue:
Description:Each of the domains in the EORTC QLQ-C30 will be scored per the assessment's scoring algorithm and summarized using descriptive statistics at baseline
Measure:Correlation of cytokines levels with clinical outcomes
Time Frame:At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer.
Safety Issue:
Description:Using a series of biomarker analysis for cytokines, including G-CSF and MCP1 proteins in the plasma
Measure:Correlation of circulating mutated DNA levels with clinical outcomes
Time Frame:At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer.
Safety Issue:
Description:Using a series of biomarker analysis for circulating mutated DNA
Measure:Correlation of chemokines levels (pg/mL) with clinical outcomes
Time Frame:At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer.
Safety Issue:
Description:Using a series of biomarker analysis for chemokines, including: IL-2, IL-4, IL-5, IL-10, TNF-α, IFN-γ
Measure:Correlation of Alpha-feto-protein levels(ng/mL) with clinical outcomes
Time Frame:At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer.
Safety Issue:
Description:Using a series of biomarker analysis for alpha-feto-protein
Measure:Correlation of HBV serologic markers levels with clinical outcomes
Time Frame:At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer.
Safety Issue:
Description:Using a series of biomarker analysis for HBV serologic markers
Measure:Correlation of HBV viral load (IU/mL) levels with clinical outcomes
Time Frame:At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer.
Safety Issue:
Description:Using a series of biomarker analysis for HBV viral load
Measure:Correlation of plasma metabolomics levels with clinical outcomes
Time Frame:At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer.
Safety Issue:
Description:Using a series of biomarker analysis for plasma metabolomics
Measure:Effects of YIV-906 on mean Cmax (mg/mL) of sorafenib in blood
Time Frame:On Day 1 of Cycle 1 (4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration.
Safety Issue:
Description:PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
Measure:Effects of YIV-906 on mean Tmax (Hr) of sorafenib in blood
Time Frame:On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration.
Safety Issue:
Description:PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
Measure:Effects of YIV-906 on mean AUC0-24(mg*h/L) of sorafenib in blood
Time Frame:On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration.
Safety Issue:
Description:PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
Measure:Effects of YIV-906 on mean AUC from time 0 to the end of the dosing period AUC0-tau (mg*h/L) of sorafenib in blood
Time Frame:On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration.
Safety Issue:
Description:PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
Measure:Effects of YIV-906 on mean t½ (Hr) of sorafenib in blood
Time Frame:On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration.
Safety Issue:
Description:PK is optional and limited to the first 15 male and 15 female patients from China study sites.
Measure:The amounts of E.coli of the human gastrointestinal tract in comparison with efficacy and toxicity in each arm, both pre-, post-treatments and control arm
Time Frame:At baseline, and then at the end of every course (4 weeks) until the end of study. Assessed up to 24 months.
Safety Issue:
Description:Samples will be collected from patients' buccal mucosa, and upper gingival; and analyzed by NGS and RT-PCR

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Yiviva Inc.

Trial Keywords

  • Adult Primary Hepatocellular Carcinoma
  • Advanced Adult Primary Liver Cancer
  • Advanced Adult Hepatocellular Carcinoma
  • BCLC Stage B Adult Hepatocellular Carcinoma
  • BCLC Stage C Adult Hepatocellular Carcinoma
  • Hepatitis B (+) Associated Advanced Hepatocellular Carcinoma
  • Child-Plough A Hepatocellular Carcinoma

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